We have shown that QTL for both bone mineral density (BMD) and structure appear to be sex-specific. These potentially important findings will be corroborated by enlarging the current sample size of brothers from 700 to 1,000 pairs and comparing these with data we have collected in 1,225 sister pairs. Bone size is an important factor in determining bone strength and hence fracture risk. We have shown that there is a significant increase in the rate of bone expansion at the femoral neck that it is heritable, and that linkage analysis has identified a number of QTL. No comparable data have been collected in men. We will perform a 5 year longitudinal study in brother pairs to establish if there are sex-specific genes for expansion of bone size. Quantitative computerized tomography (CT) at the proximal femur provides volumetric BMD of cortical and trabecular bone, structural phenotypes, and mechanical phenotypes related to in vivo bone strength. We have found significant differences between white and black men in cortical BMD. In women, we have found QTL for cortical and trabecular volumetric BMD at femoral neck. To corroborate these key findings we propose to increase our sample size by 300 pairs of brothers and 300 pairs of sisters for CT phenotypes. Achievement of these specific aims will provide fundamental information on the presence of sex-specific genes underlying the normal variation in bone density, bone structure, and in vivo biomechanical phenotypes, all key components of bone strength and risk of fracture. Further, it will provide information on the genes underlying differences in bone strength between American whites and blacks. It is expected that these proposed studies will greatly contribute to our understanding for the reasons for the higher risk of osteoporotic fracture in women than men and in American whites than blacks. Importantly the genes responsible for these differences are likely to provide targets for novel and more specific therapy aimed at prevention and treatment of osteoporotic fracture.